Distributed automated manufacturing of pluripotent stem cell products.
Distributed automated manufacturing of pluripotent stem cell products.
复制标题
多能干细胞产品的分布式自动化制造。
DOI：
10.1007/s00170-019-04516-1
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Shariatzadeh M
中科院分区：
文献类型：
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作者：
Shariatzadeh M
确定如何有效地制造细胞疗法是一个行业级的问题。分散式制造越来越重要，医疗监管机构认识到其挑战，并特别关注偏差和可比性问题。本文首次报告了在自动化三个国际工厂分散制造环境中实施人类多能干细胞（hPSC）扩增时遇到的偏差和其他风险。一项实验性示范项目在法国、德国和英国的三个开发中心使用CompacT SelectT（Sartorius Stedim，Royston，UK）自动化细胞培养平台扩增了人胚胎癌细胞系（2102 Ep）。工厂之间的预期差异涵盖材料输入、工艺本身的特征和生产系统细节，包括不同的质量管理系统和人员。在可能的情况下，通过实施包括标准化、细胞库支原体检测以及特定工程和工艺改进在内的策略来预先解决这些问题。然而，尽管采取了这些措施，但各研究中心之间仍发生了意外偏差，包括软件不兼容性和机器/过程错误以及非特征性污染。许多只是在工艺验证或工艺运行期间才变得明显。此外，包括生长速率和活力差异在内的参数只能在运行后确定，从而阻止了“实时”纠正措施。这项工作证实了药品生产质量管理规范（GMP）生产环境中通常采用的方法的关键性，并特别强调了生产系统中包括的监测步骤的要求。实时过程监控加上精心构建的质量体系对于多个现场工作至关重要，包括明确决策角色。此外，过度依赖处理后目视显微镜比较具有重大局限性;非专家难以检测有害的培养物变化，并且这种检测缓慢。
Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site–decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production system details including different quality management systems and personnel. Where possible, these were pre-addressed by implementing strategies including standardisation, cell bank mycoplasma testing and specific engineering and process improvements. However, despite such measures, unexpected deviations occurred between sites including software incompatibility and machine/process errors together with uncharacteristic contaminations. Many only became apparent during process proving or during the process run. Further, parameters including growth rate and viability discrepancies could only be determined post-run, preventing ‘live’ corrective measures. The work confirms the critical nature of approaches usually taken in Good Manufacturing Practice (GMP) manufacturing settings and especially emphasises the requirement for monitoring steps to be included within the production system. Real-time process monitoring coupled with carefully structured quality systems is essential for multiple site working including clarity of decision-making roles. Additionally, an over-reliance upon post-process visual microscopic comparisons has major limitations; it is difficult for non-experts to detect deleterious culture changes and such detection is slow.